Parkinson's (PA) disease is a neurodegenerative disease showing motor dysfunction as a cardinal symptom. It was first described in 1817 by Doctor James Parkinson, and frequently develops in elderly people. It is a highly universal disease developed with a prevalence today of about 100 in 100,000 people. First, pathomorphological studies of PA disease revealed degeneration and falling off of nerve cells in the nigra-striatum system, and neurobiochemical studies in the latter half of the 1950s revealed that the neurotransmitter of the nerves in the nigra-striatum system is dopamine (hereinafter DA), and severe deficiency of DA was found in PA disease. As a result, a concept has been established that PA disease is a striatal dopamine deficiency syndrome caused by degeneration of DA nerves in the nigra-striatum system.
The above concept was further supported since effectiveness of a DA supplementation therapy with L-dihydroxy-phenylalanine (L-DOPA), which is a DA precursor amino acid, was shown. Elucidative studies of PA disease progressed thereafter, and it is now recognized that PA disease also accompanies denaturation and hypofunction of norepinephrine (hereinafter NE) in the nerve system, though the main lesion is denaturation and hypofunction of the DA nerve system, since denaturation of pons locus-coeruleus, which is a NE nerve, and decrease of DA β-hydroxylase (hereinafter DBH), which is a NE biosynthetic enzyme, are also observed.
Symptoms associated with PA disease are principally divided into symptoms of four limbs (segmental symptoms) and truncal symptoms (axial symptoms). The segmental symptoms are classified into the symptoms of tremor and rigidity, and the axial symptoms are classified into the symptoms of freezing of gait, gait disturbance, abnormal postural sway and so on. The former syndrome of segmental symptoms is attributed to dysfunction of the DA nerve system, since L-DOPA therapy is effective for these symptoms. However, the latter syndrome of axial symptoms, particularly freezing of gait, includes an L-DOPA therapy responsive type and non-responsive type, where the non-responsive type may be ascribed to wide neurodegeneration other than of dopamine neurons.
Based on the above-mentioned main onset mechanism of PA diseases, a previous drug therapy (i.e., use of a DA nerve system activator) has been tried. To be precise, since DA itself cannot cross the blood brain barrier (hereinafter BBB), DA administered peripherally cannot replenish deficient DA in the brain.
On the other hand, since the physiological precursor amino acid, L-DOPA, can penetrate into the brain and is converted there to DA by decarboxylation by aromatic amino acid decarboxylase (hereinafter AADC), it can replenish intracerebral DA deficiency in PA disease (which is the principle of L-DOPA therapy).
Thus, L-DOPA therapy introduced in the 1970s as a treatment method of PA disease still remains the main therapy for PA disease, and a combination drug with peripheral decarboxylase inhibitor (hereinafter DCI) is prevalent at present.
The combination drug with DCI inhibits formation of DA due to decarboxylation in the periphery, which suppresses side effects caused by peripheral DA, such as nausea, vomiting, hypotension and so on, as well as suppresses peripheral L-DOPA inactivation. Therefore, a greater amount of L-DOPA can be transferred into the brain, and the same dose of L-DOPA can enhance the effect and prolong duration of effectiveness, or the same effect can be provided by the administration of a smaller amount. The effect of the latter case can be regarded an economizing effect and DCI providing such effect is sometimes called an economizer.
In addition, as a therapeutic agent for PA disease, a variety of DA nerve system activators have been developed besides L-DOPA preparations. That is, various DA receptor stimulants, DA release enhancers, and L-DOPA activators have been put into practice. These DA neuron activators are used instead of L-DOPA preparations or in combination therewith. Moreover, various anticholinergic agents having an antitremor action have long been used for the treatment of PA disease. Recent new medicaments include monoamine oxidase-type B (hereinafter MAO-B) inhibitors and catechol-O-methyl group transferase inhibitors (hereinafter COMT inhibitor). These drugs are classified as economizers since they enhance administration efficiency by inhibiting an enzyme reaction that inactivates L-DOPA and generates DA. Entacapone, which is a COMT inhibitor recently introduced into the market, was approved for an indication of improving on the decrease of efficacy duration due to a long-term administration in the L-DOPA therapy and diurnal variation (known as “wearing-off phenomenon”) where a drug suddenly becomes ineffective.
Based on the secondary onset mechanism of the PA disease, a therapeutic agent for PA disease by a NE nerve system activator has also been tried. Among them, DOPS (general name, Droxidopa) has a unique position.
While DOPS is a nonphysiological amino acid, it is an NE precursor amino acid which is decarboxylated by aromatic amino acid decarboxylase (AADC) and converted to physiological NE. That is, it is assumed that aromatic amino acid DOPS penetrates into the brain, is converted to NE within the brain, replenishes intracerebral NE, and contributes to the treatment of PA disease.
On the other hand, L-DOPA therapy does not provide a significant effect on axial symptoms such as freezing of gait and the like in PA disease. Therefore, Narabayashi et al. (Proc. Japan Acad., 57, Ser. B, No. 9, 351-354(1981)) postulated that these axial symptoms might be due to dysfunction of the NE nerve system. To activate the NE nerve system, he tried administration of racemic DOPS to patients with PA disease with the “freezing of gait symptom”, and clinically observed its effect for the first time.
In Japan, the effect was continuously studied by using DOPS in an optically active form, and DOPS was finally approved in 1989 based on the clinical trial results significantly superior to that of placebo, in double-blind comparison using placebo as a control (see Narabayashi et al., “clinical evaluation” vol. 15 (No. 3) 423-457(1987): Clin. Eval., 15: 423-457, 1987, October). However, the efficacy rate of DOPS was not necessarily high. In the Societas Neurologica Japonica PA disease guideline, therefore, DOPS is regarded as a medicament to be optionally tried, and its effectiveness was questioned outside Japan.
The reason for the limited effect of DOPS is considered to be attributable to low conversion efficiency of DOPS as an amine precursor to NE as compared to L-DOPA. That is, as compared to L-DOPA, the decarboxylation reaction rate of DOPS is low, and transferability of DOPS into the brain is low, based on which facts, a negative report has been documented that DOPS cannot be expected as an intracerebral NE precursor amino acid (see G. Bartholini et al., J. Pharmacology & Experimental Therapeutics, 193, 523-532(1975)).
In view of the foregoing, the development of a therapeutic agent and a treatment method for the improvement and treatment of axial symptoms (particularly, freezing of gait) of patients with PA disease, for which L-DOPA therapy is ineffective, has been desired.